3-54918704-C-G

Position:

• chr3-54918704-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020678.4(LRTM1):​c.793G>C​(p.Glu265Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,614,132 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (9 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (11 hom.)
• Consequence: LRTM1 NM_020678.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.117

Genes affected

LRTM1 (HGNC:25023): (leucine rich repeats and transmembrane domains 1) Predicted to enable Roundabout binding activity and heparin binding activity. Predicted to be involved in axon guidance and negative chemotaxis. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029322207).
• BP6: Variant 3-54918704-C-G is Benign according to our data. Variant chr3-54918704-C-G is described in ClinVar as [Benign]. Clinvar id is 709209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00639 (973/152258) while in subpopulation AFR AF= 0.0215 (893/41562). AF 95% confidence interval is 0.0203. There are 9 homozygotes in gnomad4. There are 446 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRTM1	NM_020678.4	c.793G>C	p.Glu265Gln	missense_variant	3/3	ENST00000273286.6	NP_065729.1
CACNA2D3	NM_018398.3	c.2449+18836C>G		intron_variant		ENST00000474759.6	NP_060868.2
LRTM1	NM_001304389.2	c.565G>C	p.Glu189Gln	missense_variant	3/3		NP_001291318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRTM1	ENST00000273286.6	c.793G>C	p.Glu265Gln	missense_variant	3/3	1	NM_020678.4	ENSP00000273286.5
CACNA2D3	ENST00000474759.6	c.2449+18836C>G		intron_variant		1	NM_018398.3	ENSP00000419101.1

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 965 AN: 152140 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00198 AC: 498 AN: 251276 Hom.: 7 AF XY: 0.00149 AC XY: 203 AN XY: 135820

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000755 AC: 1104 AN: 1461874 Hom.: 11 Cov.: 32 AF XY: 0.000656 AC XY: 477 AN XY: 727236

Gnomad4 AFR exome AF: 0.0248

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00639 AC: 973 AN: 152258 Hom.: 9 Cov.: 31 AF XY: 0.00599 AC XY: 446 AN XY: 74458

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.00757

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.92
DANN	Benign	0.75
DEOGEN2	Benign	0.0038	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.024
Sift	Benign	0.35	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0020	B;.
Vest4		0.061
MVP		0.21
MPC		0.016
ClinPred		0.00050	T
GERP RS		0.28
Varity_R		0.051
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61735200; hg19: chr3-54952731;